Our goal is to determine the mechanism of abnormal brain function in severe liver disease. Toward this end we have two approaches: 1) to identify and isolate potentially toxic agents in the blood and spinal fluid of patients with hepatic coma, and 2) to examine the enzymes and substrates involved in cerebral ammonia metabolism in experimental animals rendered acutely and chronically hyperammonemic. Cerebrospinal fluid of patients with demonstrated liver disease will be analyzed for concentrations of ammonia, glutamine, glutamate, GABA and alpha-ketoglutaramate (alpha-KGM). Particular attention will be devoted to establishing whether or not (alpha-KGM levels in CSF 1) are diagnostic of hepatic failure, 2) correlate with the severity of neurological impairment, and 3) when elevated, can exert a direct neurotoxic action. Activities of the principal enzymes involved in the metabolism of alpha-KGM (i.e., glutamine transaminase and omega-amidase) will be determined in post-mortem brain samples of hepatic and non- hepatic patients, and attempts will be made to purify the enzymes from human brain tissue. As an experimental model of chronic hyperammonemia, portocaval shunts will be performed on a colony of rats; at 3-week intervals after surgery the brains and spinal fluid will be analyzed for alpha-KGM, ammonia and glutamine contents, and the brains evaluated neuropathologically. The aim will be to determine whether ammonia, per se, or some product of ammonia detoxification is responsible for the astrocytic changes (Alzheimer's Types I & II) associated with chronic hepatic disease.